Calcium slow channel blocking agents are a structurally diverse group of compounds known to depress heart function by blocking inward calcium current, though additional subcellular sites of action have also been suggested. The proposed research will test the efficacy of several Ca2+ slow channel blocking agents in reducing the damage to heart muscle due to ischemia and subsequent reperfusion. These experiments will help to define which of these compounds have the greatest potential for direct pharmacological preservation of heart muscle tissue. In addition, an assessment of whether or not the Ca2+ antagonists reduce ischemic damage by decreasing Ca2+ currents or through effects on other cellular processes will be made by comparing the influence of Ca2+ antagonists and perfusate containing reduced Ca2+ content on the recovery of heart function. Cardioplegic effects will be indicated if there is preservation of tissue energy stores and correlation of energy levels with return of function after ischemia. Other subcellular actions will be indicated if there are differences in recovery with equally cardioplegic treatments, of if noncardioplegic doses improve recovery. Other subcellular sites of protection to be examined include mitochondria and sarcolemma. The studies will employ the global ischemic model of the isolated, perfused, working rat heart. Heart function is qualified from the pressure and rate of heart beat, and the energy reserves are determined by enzymatic analysis of tissue extracts. Mitochondrial function is assessed polarographically, and sarcolemmal integrity by creatine phosphokinase release, and cellular Ca2+ and water accumulation. The long term objectives of my research are to determine whether or not Ca2+ has an influence on ischemic injury, and if so, to define its role in the cellular pathophysiology of ischemic injury and to develop pharmacologic interventions to reduce the damage. The approach combines physiological, biochemical, and pharmacological techniques. The findings will have direct application to the preservation of heart muscle in ischemia and heart surgery where the same perfusion conditions are employed.